Post on 15-Feb-2019
Allemani, C; Sant, M; Weir, HK; Richardson, LC; Baili, P; Storm,H; Siesling, S; Torrella-Ramos, A; Voogd, AC; Aareleid, T; Ardanaz,E; Berrino, F; Bielska-Lasota, M; Bolick, S; Cirilli, C; Colonna, M;Contiero, P; Cress, R; Crocetti, E; Fulton, JP; Grosclaude, P; Haku-linen, T; Izarzugaza, MI; Malmstrm, P; Peignaux, K; Primic-akelj,M; Rachtan, J; Safaei Diba, C; Snchez, MJ; Schymura, MJ; Shen, T;Traina, A; Tryggvadottir, L; Tumino, R; Velten, M; Vercelli, M; Wolf,HJ; Woronoff, AS; Wu, X; Coleman, MP (2013) Breast cancer sur-vival in the US and Europe: A CONCORD high-resolution study. In-ternational journal of cancer Journal international du cancer, 132 (5).pp. 1170-81. ISSN 0020-7136 DOI: https://doi.org/10.1002/ijc.27725
Downloaded from: http://researchonline.lshtm.ac.uk/103753/
DOI: 10.1002/ijc.27725
Usage Guidelines
Please refer to usage guidelines at http://researchonline.lshtm.ac.uk/policies.html or alterna-tively contact researchonline@lshtm.ac.uk.
Available under license: Copyright the publishers
Breast cancer survival in the US and Europe: a CONCORD high-resolution study
Claudia Allemani, PhD1,2, Milena Sant, MD2, Hannah K Weir, PhD3, Lisa C Richardson, MD3, Paolo Baili, PhD4, Hans Storm, MD5, Sabine Siesling, PhD6, Ana Torrella-Ramos, MD7, Adri C Voogd, PhD8, Tiiu Aareleid, MD9, Eva Ardanaz, PhD10, Franco Berrino, MD11, Magdalena Bielska-Lasota, MD12, Susan Bolick, MSPH13, Claudia Cirilli, BSc14, Marc Colonna, PhD15, Paolo Contiero, PhD16, Rosemary Cress, DrPH17, Emanuele Crocetti, MD18, John P Fulton, PhD19, Pascale Grosclaude, MD20, Prof Timo Hakulinen21, M Isabel Izarzugaza, MD22, Prof Per Malmström23, Karin Peignaux, PhD24, Maja Primic-Žakelj, MD25, Prof Jadwiga Rachtan26, Chakameh Safaei Diba, MD27, Maria-José Sánchez, MD28, Maria J Schymura, PhD29, Tiefu Shen, MD30, Adele Traina, MD31, Prof Laufey Tryggvadottir32,33, Rosario Tumino, MD34, Michel Velten, MD35, Marina Vercelli, PhD36,37, Holly J Wolf, PhD38, Anne-Sophie Woronoff, MD39, Xiaocheng Wu, MD40, and Prof Michel P Coleman1
1Cancer Research UK Cancer Survival Group, Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK 2Analytical Epidemiology Unit, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, I-20133 Milan, Italy 3Division of Cancer Prevention and Control, Centers for Disease Control and Prevention, 4770 Buford Highway NE, MS-K53 Atlanta, GA 30341-3742, USA 4Descriptive Studies and Health Planning Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, via Venezian 1, I-20133 Milan, Italy 5Department of Cancer Prevention and Documentation, Danish Cancer Society, Strandboulevarden 49, Copenhagen Ø, Denmark 6Netherlands Cancer Registry, Comprehensive Cancer Centre the Netherlands, PO Box 19079, 3501 DB Utrecht, The Netherlands 7Cancer Registry Castellón (Comunitat Valenciana), Avenida del Mar 12, E-12003 Castellón, Spain 8Department of Research, Eindhoven Cancer Registry, PO Box 231, 5600 AE Eindhoven, The Netherlands 9Department of Epidemiology and Biostatistics, National Institute for Health Development, Hiiu St 42, 11619 Tallinn, Estonia 10Navarra Cancer Registry, Navarra Public Health Institute (CIBERESP), C Leyre 15, 31003 Pamplona, Navarra, Spain 11Unit of Etiological Epidemiology and Prevention, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan Italy 12Bioethics and Health Psychology Unit, Department of Health Promotion and Postgraduate Education, National Institute of Public Health, National Institute of Hygiene, 24 Chocimska str, 00-791 Warsaw, Poland 13South Carolina Central
Corresponding author: Claudia Allemani PhD, Lecturer in Cancer Epidemiology, Cancer Research UK Cancer Survival Group, Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK, claudia.allemani@lshtm.ac.uk Tel: +44 (0)20 7927 2855.
Novelty and impact of the work: Most of the diagnostic and therapeutic modalities used for breast cancer more than 10 years ago remain in widespread use today. Understanding the extent to which access to those modalities can explain international differences in cancer survival therefore remains highly relevant. This is the largest population-based high-resolution study, with a common protocol, standard quality-control procedures and central analyses. The modelling approach to estimate net survival is a methodological strength.
HHS Public AccessAuthor manuscriptInt J Cancer. Author manuscript; available in PMC 2016 January 09.
Published in final edited form as:Int J Cancer. 2013 March 1; 132(5): 1170–1181. doi:10.1002/ijc.27725.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Cancer Registry, 2600 Bull St. Columbia, SC 29201, United States 14Modena Cancer Registry, Via Del Pozzo 71, Modena, Italy 15Isère Cancer Registry, 21 Chemin des Sources, F-38241 Meylan, France 16Cancer Registry and Environmental Epidemiology Unit, Fondazione IRCSS Istituto Nazionale Tumori, Via Venezian 1, I-20133 Milan, Italy 17Public Health Institute/California Cancer Registry,1825 Bell Street, Suite 102, Sacramento, CA 95825, United States 18Tuscany Cancer Registry, UO Epidemiologia Clinica e Descrittiva – ISPO, Via di San Salvi 12, I-50135 Firenze, Italy 19Rhode Island Cancer Registry, 3 Capitol Hill, Room 403, Providence, RI 02908-5097, United States 20Tarn Cancer Registry, Chemin des Trois Tarn, F-81000 Albi, France 21Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Pieni Roobertinkatu 9, FI-00130 Helsinki, Finland 22Registros e Información Sanitaria, Dpto. de Sanidad del Gobierno Vasco, c Donostia-San Sebastian, E-01010 Vitoria-Gasteiz, Spain 23Skåne Department of Oncology, Skåne University Hospital, S 221 85 Lund, Sweden 24Côte d’Or Breast and Gynaecologic Cancer Registry, Centre Georges-François Leclerc, Dijon, France 25Epidemiology and Cancer Registry, Institute of Oncology Ljubljana, Zaloska 2,1000 Ljubljana, Slovenia 26Cracow Cancer Registry, Centre of Oncology, M Skłodowska-Curie Memorial Institute, Garncarska 11, 31-115 Krakow, Poland 27National Cancer Registry of Slovakia, National Health Information Center, Lazaretska 26, 811 09 Bratislava, Slovakia 28Andalusian School of Public Health (Granada, Spain) and CIBER de Epidemiología y Salud Pública, Madrid, Spain 29New York State Cancer Registry, 150 Broadway, Suite 361, Menands, NY 12204-2719, United States 30Illinois State Cancer Registry, 525-535 W. Jefferson St. Springfield, IL 62761, United States 31Department of Oncology, P.O. M. Ascoli, ARNAS-Civico, Palermo, Italy 32Faculty of Medicine, University of Iceland, Reykjavik, Iceland 33Icelandic Cancer Registry, Skogarhlid 8, PO Box 5420, 125 Reykjavik, Iceland 34Cancer Registry and Histopathology Unit, Civile-MP Arezzo Hospital, ASP Ragusa, Piazza Igea 1, I-97100 Ragusa, Italy 35Laboratoire d’épidémiologie et de santé publique, Registre des cancers du Bas-Rhin, Faculté de médecine-Université de Strasbourg, 4 rue Kirschleger, F-67085 Strasbourg, France 36UOS Epidemiologia Descrittiva, USM-IST (IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro), Largo R Benzi, 10-CBA, Torre C1, 16132 Genova, Italy 37Sez. Epidemiologia Descrittiva, Dipartimento di Scienze della Salute, Università di Genova, Via A. Pastore 1, USM-IST/UNIGE, Genova, Italy 38Colorado School of Public Health,13001 E. 17th Place, Bldg 500, Room E4308, Aurora, CO 80045, United States 39Doubs Cancer Registry, University Hospital Besançon, 2 Place Saint-Jacques, F-25030 Besançon Cédex, France 40Louisiana Tumor Registry, LSUHSC School of Public Health, 2020 Gravier St. 3rd Floor, New Orleans, LA 70112, United States
Abstract
Breast cancer survival is reportedly higher in the US than in Europe. The first worldwide study
(CONCORD) found wide international differences in age-standardised survival. The aim of this
study is to explain these survival differences.
Population-based data on stage at diagnosis, diagnostic procedures, treatment and follow-up were
collected for about 20,000 women diagnosed with breast cancer aged 15–99 years during 1996–98
in 7 US states and 12 European countries. Age-standardised net survival and the excess hazard of
Allemani et al. Page 2
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
death up to five years after diagnosis were estimated by jurisdiction (registry, country, European
region), age and stage with flexible parametric models.
Breast cancers were generally less advanced in the US than in Europe. Stage also varied less
between US states than between European jurisdictions. Early, node-negative tumours were more
frequent in the US (39%) than in Europe (32%), while locally advanced tumours were twice as
frequent in Europe (8%), and metastatic tumours of similar frequency (5–6%). Net survival in
Northern, Western and Southern Europe (82–85%) was similar to that in the US (84%), but lower
in Eastern Europe (72%). For the first 3 years after diagnosis the mean excess hazard was higher
in Eastern Europe than elsewhere: the difference was most marked for women aged 70–99 years,
and mainly confined to women with locally advanced or metastatic tumours.
Differences in breast cancer survival between Europe and the US in the late 1990s were mainly
explained by lower survival in Eastern Europe, where low healthcare expenditure may have
constrained the quality of treatment.
Keywords
CONCORD; net survival; excess hazard; cancer registries
Introduction
Breast cancer survival has been reported as higher in the US than in Europe1,2. For women
diagnosed 1985–89, five-year survival was higher in each of the nine Surveillance,
Epidemiology and End Results (SEER) areas than in any of the 22 European countries
participating in the EUROCARE-2 study.
The first worldwide analysis of cancer survival (CONCORD3) provided a systematic
comparison of survival for adults (15–99 years) diagnosed with a cancer of the breast, colon,
rectum or prostate in one of 31 countries during 1990–94 and followed up to 1999.
International differences in age-standardised survival were very wide, even after adjustment
for differences in mortality from other causes of death. Breast cancer survival in the US and
Canada was higher than in other countries, but differences between the US and most
European regions were smaller than for women diagnosed during 1985–892. The largest
differences were between the US and Eastern Europe.
A population-based comparison of five-year breast cancer survival among women diagnosed
in 17 territories in 6 European countries during 1990–92 and in the 9 states and metropolitan
areas of the US covered by the SEER programme in 1990 showed that differences were
mainly attributable to stage at diagnosis and the diagnostic procedures used to determine the
stage4.
Both the assiduity of investigation and the appropriateness of treatment by stage varied
widely for women diagnosed in Europe during 1990–92 and 1996–985,6. Primary treatment
for breast cancer also varies greatly throughout the US7,8. Following the NIH Consensus
Development Conference in 1990, which recommended breast-conserving surgery and
radiotherapy instead of mastectomy for women with stage I and II breast cancer, the
Allemani et al. Page 3
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
proportion treated with breast-conserving surgery increased steadily up to 19959, but the
percentage who also received radiotherapy and/or axillary lymphadenectomy declined10.
Differences in protocol and calendar period make it difficult to draw firm conclusions from
these studies about whether the differences in survival between Europe and the US are
attributable to differences in stage, or treatment, or both.
The CONCORD protocol incorporated “high-resolution” studies designed to explain the
international variations in survival for breast, colorectal and prostate cancer. The analyses
involve large random samples of patients, with detailed clinical and pathological data that
are not routinely abstracted by population-based cancer registries. The study reported here
provides a trans-Atlantic comparison of stage, treatment and survival for women with breast
cancer. The aims were to compare the stage distributions in Europe and the US; to determine
whether the transatlantic differences in 5-year survival persist and, if so, to assess the extent
to which they are attributable to differences in stage. We also set out to compare adherence
to “standard care” for breast cancer in relation to age, stage and hormone receptor status,
before widespread introduction of clinical guidelines.
Material and methods
Data on stage, diagnostic procedures, treatment and follow-up were collected for a
representative sample of about 20,000 women aged 15–99 years who were registered with a
diagnosis of breast cancer in the US or one of 12 European countries during 1996–98. A
common protocol was used, based on the EUROCARE high-resolution protocols5,6.
The European data were provided by 26 population-based cancer registries in 12 countries, 7
of which with national coverage, denoted by an asterisk (*). For some analyses, the data
were grouped into four European regions defined by the United Nations (UN, http://
unstats.un.org/unsd/methods/m49/m49regin.htm) - Northern Europe: Denmark*, Finland*,
Iceland*, Sweden*; Western Europe: France (Bas-Rhin, Côte d’Or, Doubs, Isère, Tarn) and
the Netherlands (Eindhoven, North East Netherlands); Southern Europe: Italy (Firenze,
Genova, Modena, Palermo, Ragusa, Varese), Slovenia*, Spain (Basque Country, Castellon,
Granada, Navarra); Eastern Europe: Estonia*, Poland (Cracow, Warsaw), Slovakia*.
Estonia is classified by the UN as being in Northern Europe, but cancer survival has usually
resembled that in Eastern European countries11, and the data from Estonia are included here
with Eastern Europe. Data from the US were provided by 7 state-wide registries: California,
Colorado, Illinois, Louisiana, New York, Rhode Island and South Carolina. The US
registries are part of the National Program of Cancer Registries, based at the Centers for
Disease Control and Prevention.
For this study the cancer registries included in the EUROCARE-3 high-resolution study6
made special efforts to update the follow-up to at least five years after diagnosis for all
patients. The North East Netherlands registry was not included in EUROCARE-3, but it is
unusual in that it routinely collects almost all the data required for high-resolution studies on
all registered cancer patients, so it was able to provide such data on virtually all women with
breast cancer, not just a sample.
Allemani et al. Page 4
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Most European registries provided a random sample of at least 500 women diagnosed during
1996–98, as specified by the protocol. Denmark and Sweden provided a sample of women
diagnosed in 1994, and Palermo (Italy) provided data for all women diagnosed in 1999, the
first year for which data were available there. The Finnish cases were a population-based
sample of women diagnosed in the Tampere hospital region, which is considered
representative of the whole of Finland. Despite these slight departures from protocol, these
cases were retained to ensure the widest possible geographic coverage. Each of the US
registries provided a random sample of at least 500 women diagnosed with breast cancer in
1997.
Anonymised, individual cancer registration records were supplied for 20,150 women
diagnosed with a malignant neoplasm of the breast. In situ tumours (1,168, 5.8%) were
excluded from the analyses because they were collected systematically in the US, but not in
Europe. A further 20 cases (0.1%) were excluded because they did not meet the protocol (2
with benign or uncertain behaviour, 2 with the morphology of leukaemia or lymphoma, and
16 aged less than 15 or more than 100 years). In all, 18,962 women with a primary, invasive,
malignant neoplasm of the breast were included in the analysis of stage and treatment.
Women whose cancer was only registered from a death certificate (23; 0.1%), or of
unknown vital status (18; 0.1%), or for whom the date of last known vital status preceded
the date of diagnosis (32; 0.2%), were excluded from the survival analyses, which thus
involved 18,889 women.
Information on stage, diagnostic examinations, treatment and follow-up was obtained by
direct examination of the clinical record. Where records were incomplete, pathology reports,
hospital discharge records and other sources were consulted as necessary.
Disease stage was defined according to the 4th edition of the TNM (Tumour, Nodes,
Metastasis) manual.12 If pathological data on tumour size and lymph node status (pT and
pN) were unavailable, clinical data (cT and cN) were used. Following advice from
epidemiologists, pathologists and clinicians, records for which the metastatic status was
unknown (MX) were considered as negative (M0), if T and N were known. Patients were
grouped into six categories: early, node-negative disease (T1N0M0), larger node-negative
(T2-3N0M0), node-positive (T1-3N+M0), locally advanced (T4, any N, M0), metastatic
(M1) and unstaged. Within the category of early, node-negative disease, we also assessed
the distribution of small tumours by size: less than 5mm (T1a), 5–10mm (T1b) and over
10mm and up to 20mm (T1c). Estrogen-receptor (ER) status was categorized as positive,
negative or unknown. Age at diagnosis was categorised into four groups (15–39, 40–49, 50–
69, 70–99 years) for survival analysis. Treatment comparisons were made in wider age
groups: 15–49 and 50–99 years for chemotherapy and hormone therapy; 15–69 and 70–99
years for breast-conserving surgery plus radiotherapy.
Data on surgical procedures were collected in 7 categories: conservative surgery (including
quadrantectomy, tumour excision, lumpectomy), simple mastectomy, any modified radical
mastectomy, extended radical (Halsted) mastectomy, surgery (not otherwise specified),
unknown if surgery was performed, and no surgery. When a surgical procedure was
performed, axillary procedures were collected in 5 categories: for lymph-node sampling, for
Allemani et al. Page 5
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
axillary clearance, unspecified whether for sampling or clearance, not specified if done or
not, and not done. Information was also sought on sentinel lymph-node biopsy, with or
without lymphadenectomy, but sentinel biopsy was very uncommon during 1996–98.
Information on biopsy or needle aspiration of the breast was coded in 5 categories as either
done; not done because of refusal or death, or for specified medical contraindications, or for
other or unspecified reasons; or unknown if done or not. Chemotherapy, radiotherapy and
hormonal therapy were coded as yes, no or unknown.
Primary treatment for early node-negative disease was dichotomised as breast-conserving
surgery with radiotherapy (BCS+RT) vs. all other surgical procedures, whether or not
followed by radiotherapy. Chemotherapy and endocrine treatment were dichotomised as
administered vs. not administered or unknown.
Statistical Analysis
We examined the proportion of women with early, node-negative disease who received
breast-conserving surgery plus radiotherapy; the proportion of women with node-positive
disease who received chemotherapy; the proportion of women with estrogen-receptor-
positive tumours who received tamoxifen, and the proportion of women for whom at least
10 lymph nodes were removed and examined during lymphadenectomy, as recommended in
the TNM manual for staging breast cancer from 1992 (4th edition, 2nd revision)12. Cancer
registry data sets were excluded if data on stage and/or treatment were missing for 20% or
more of patients. Thus Firenze and Ragusa were excluded from the analyses of
chemotherapy in node-positive disease, and Firenze, Genova and Ragusa were excluded
from the analyses of hormonal treatment in estrogen-receptor-positive disease.
Net survival up to five years after diagnosis was estimated by jurisdiction (registry, country
and European region), age and stage using flexible parametric excess hazard models13. Net
survival is the survival of cancer patients in the hypothetical situation when the cancer may
be assumed to be the only possible cause of death; it may be interpreted as cancer survival
after controlling for competing causes of death. Net survival was estimated with a modelling
approach14,15, in which the total hazard of death is considered as the sum of the cancer-
related mortality hazard (excess hazard), and the hazard of death from other causes
(background hazard). The background hazard is derived from life tables of all-cause
mortality by sex, single year of age and calendar year in the general population of the
country, region or (in the US) state from which the cancer patients are drawn. We
constructed period life tables for 1994–2004 with the approaches proposed by Baili et al.16.
Age was included as a continuous variable in all models, in order to avoid the bias in the
estimation of net survival that would otherwise arise from differential loss of the oldest
patients (informative censoring). Both non-linear and time-dependent (interaction with time
since diagnosis) effects of age were initially modelled with cubic splines. The
proportionality of the effect of tumour stage on the excess hazard was also assessed. Simpler
models, with linear and/or proportional effects, were successively tested and selected using
the Akaike Information Criterion for goodness of fit17. We also estimated the instantaneous
excess risk (hazard) of death due to breast cancer, after subtracting the hazard from all other
causes of death14,15,18,19. We present the mean excess hazard per 1,000 person-years at risk
Allemani et al. Page 6
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
at 1 month, 6 months and 1, 3 and 5 years since diagnosis, both by age and by stage at
diagnosis after adjustment for age.
Overall (all-ages) net survival estimates were age-standardised with the international cancer
survival standard (ICSS) weights20.
We used a logistic regression model to estimate the odds of women with early node-negative
disease receiving breast-conserving surgery and radiotherapy (vs. any other surgical
procedure, with or without radiotherapy) in each jurisdiction, after adjustment for age and
tumour size.
Survival analyses were performed with stpm218 in Stata version 11 (StataCorp LP, College
Station, TX).
Results
We included 18,962 women with invasive primary breast cancer: 15,842 women in 26
jurisdictions in 12 European countries and 3,120 women in 7 US states (Table 1).
Microscopic verification was available for 98–99% of the women in each of the US states
and 94% in Europe, ranging from 79% in Estonia to 100% in the Basque country (Spain).
Data were available on stage for about 90% of cases in both data sets, ranging from 78%
(Ragusa, Italy) to 95% or more in 8 of the 26 European registries and from 81% (New York)
to 94% (Colorado and S Carolina) in the US.
Breast cancers were generally less advanced in the US than in Europe, and the stage
distribution varied less between US states than between European jurisdictions. Early node-
negative tumours were more frequent in the US (39%, range 33–45%) than in Europe (32%,
16–49%). Large node-negative tumours were of similar frequency (Europe 14%, 9–22%; US
14%, 10–18%), while node-positive tumours were more common in Europe (33%, 25–44%)
than the US (26%, 22–29%). Locally advanced tumours were twice as frequent in Europe
(8%, 0–24%) as in the US (4%, 3–6%), but the overall frequency of metastatic tumours was
similar (5–6%). The proportion of tumours with unspecified stage was slightly higher in the
US (11%) than Europe (8%), but up to 18–22% in three European registries (Finland; Italy:
Firenze, Ragusa), while only New York (19%) differed much from the US average.
Exclusion of these registries did not substantially alter the overall stage distributions in
Europe or the US (data not shown).
Lymphadenectomy was reported for 13,687 (86%) women in Europe and 2,531 (81%) in the
US, but it was generally more extensive in the US, where 10 or more nodes were examined
in 78% (range 76–83%) of procedures, compared with 66% (23–93%) in Europe (Table 2).
Among women with early node-negative tumours, the distribution of tumour size was more
favourable in the US than in Europe.
More than 90% of women received surgical treatment: 91% in Europe (from 77% in Estonia
to 95% or more in 10 of 26 jurisdictions) and 96% in the US (93–97%; Table 3). Among
operated women, 35% had early node-negative disease in Europe, compared with 41% in the
US. Among women operated for early node-negative disease, breast-conserving surgery plus
Allemani et al. Page 7
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
radiotherapy was received by 55% in Europe and 49% in the US, but the variability was
much wider in Europe (9% in Estonia; 78–84% in four of the five French regions) than in
the US (34% in S Carolina; 58% in Rhode Island). The proportion of women aged 70–99
years who received breast-conserving surgery and radiotherapy for early node-negative
disease varied more between European countries and regions (4–6% in two Polish regions;
84% in Tarn) than between US states (21% in Louisiana; 47–48% in Rhode Island and
California).
For early node-negative disease, and relative to Southern Europe (1,848 women, reference
category), the odds of receiving both breast-conserving surgery and radiotherapy (vs. any
other surgical procedure, with or without radiotherapy), adjusted for age and tumour size,
were lower in the US (OR=0.80; 95%CI 0.69–0.94) and Northern Europe (OR=0.60; 0.50–
0.72); much lower in Eastern Europe (OR=0.16; 0.12–0.20), and higher in Western Europe
(OR=1.57; 1.36–1.81) (Table 4). The odds of receiving this treatment were significantly
lower for women aged 70–99 years than for those aged 60–69 years (OR=0.48; 0.41–0.56),
after adjustment for region and tumour size. Women with tumours of 5–10mm (T1b)
received this treatment more than women with larger tumours (up to 20mm, T1c) (OR=1.31;
1.16–1.48).
Among women with node-positive tumours, 58% received chemotherapy in the 26 European
jurisdictions, compared with 69% in the 7 US states (Table 5). Among women aged less
than 50 at diagnosis, the overall proportion was similar in Europe and the US (90%), but the
range was wider in Europe (54–100%) than the US (84–94%). Among older women, the
proportion who received chemotherapy was higher, and varied less, in the US (60%, range
53–67%) than in Europe (46%, range 14–75%).
Overall, endocrine treatment in ER-positive tumours was slightly higher in the US (62%)
than in Europe (55%). The proportion was similar in women aged 50 and over (63% in the
US; 59% in Europe), but younger women received tamoxifen more often in the US (58% vs.
44%).
Overall, age-standardised net survival at five years was 81% in Europe and 84% in the US
(Figure 1). Survival in Northern, Western and Southern Europe (81–84%) was similar to that
in the US (84%), but it was lower in Eastern Europe (69%). Survival varied more widely
between European jurisdictions (88% in Iceland to 62% in Estonia) than between US states
(from 91% in Colorado to 76% in South Carolina).
Five-year age-standardised net survival was broadly similar in all European regions and the
US for early, node-negative tumours (96–98%) and for large, node-negative tumours (85–
90%) (Figure 2, available in web-appendix). The geographic range in survival was much
wider for locally advanced disease, from 37% in Eastern Europe to 77% in Northern Europe,
and 44% in the US. As with overall survival, stage-specific five-year survival was similar in
Northern, Western and Southern Europe and the US. In Eastern Europe, survival for node-
positive, locally advanced and metastatic tumours was lower than in other European regions
or the US.
Allemani et al. Page 8
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
The mean excess hazard was higher in Eastern Europe than in other jurisdictions at 1 month,
6 months and 1, 3 and 5 years after diagnosis, both for all ages and in each of 5 age
categories (Figure 3, available in web-appendix). The difference was most marked for
women aged 70–99 years. No striking differences were found between Northern, Western,
Southern Europe and the US. The high excess hazard of death in Eastern Europe was mainly
confined to women with locally advanced or metastatic tumours (Figure 4, available in web-
appendix).
Discussion
Transatlantic differences in cancer survival have raised questions about early diagnosis and
the adequacy of investigation and treatment. To our knowledge, this is the first population-
based high-resolution study to use clinical data that were collected by trained abstractors
from the primary medical records under a common protocol, subjected to standard quality
control procedures and analysed centrally with the same statistical methods. We compared
survival using clinical data on stage, diagnostic procedures and treatment. The survival
differences appear likely to be related to differences in diagnosis and patterns of care shortly
after diagnosis. The women were diagnosed more than 10 years ago, but most diagnostic
and therapeutic approaches used at that time remain in widespread use: understanding their
role in international differences in survival remains relevant.
Overall, five-year net survival was not very different in Europe (81%) and the US (84%).
Differences were mainly confined to the three Eastern European countries, Estonia, Poland
and Slovakia, where average five-year survival was 69%. Estonia and Slovakia are both
covered by national cancer registries, and the women from those countries were thus
nationally representative. Survival varied more widely between the 26 European
jurisdictions than between the 7 US states.
The differences in survival between Europe and the US in the late 1990s are smaller than for
women diagnosed at the beginning of the decade3,4. In the previous high-resolution study4,
the US data were taken from the SEER public-use data set21 and harmonised to the extent
possible with the data collected under the EUROCARE-2 high-resolution protocol. By
contrast, the data for this study were collected directly from the clinical records using a
standard protocol; European coverage rose from 17 to 26 registries (11 contributed to both
studies), and US coverage changed from the 5 metropolitan areas and 4 states covered by the
SEER program to 7 state-wide registries in the National Program of Cancer Registries
(NPCR). Survival in the 1990s was lower in the NPCR territories than the SEER areas3,22.
Finally, in the previous high-resolution study, differences in background mortality in the US
were controlled with a single national life table for 1990, weighted for the proportion of
Blacks, Whites and other races, whereas we were able to use state-specific life tables for
each calendar year 1994–2004.
The modelling approach used to estimate net survival is a strength of this study, but it does
not explain the smaller transatlantic differences than those obtained with relative survival in
the previous study. We found similar patterns with all the other widely used methods for
survival estimation (data not shown).
Allemani et al. Page 9
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
The European differences in survival were generally similar to those reported for the same
countries among women diagnosed 1995–9911. Survival was higher than expected in
Denmark (84%): the data in this study are from eastern Denmark, greater Copenhagen and
Copenhagen (Zeeland), where most of the population has undergone mammographic
screening since 199123. In these areas, survival after mammographic diagnosis is higher than
in Denmark as a whole, regardless of whether it was a screening mammography. Survival in
Slovenia was lower than in other Southern European countries, and more similar to that in
Eastern Europe. Variation in survival between the 7 US states was less marked than in
Europe, mostly in the range 81–87%, but ranging from 91% in Colorado to 76% in South
Carolina, where Blacks represent approximately 30% of the population (http://
www.ipspr.sc.edu/publication/Older%20SC.pdf).
The availability of information about race in this data set would have strengthened the
international survival comparisons, but information about race is not available in many
European countries. Race in the US and geographical area in Europe are often considered as
a proxy for socio-economic status. In future studies, it would be preferable to use life tables
that are specific for race and/or socio-economic status.
Stage-specific net survival was similar in most European jurisdictions and US states. In
Eastern Europe, survival from node-positive, large and metastatic tumours (N+; T4; M1)
was lower than in other European regions or the US, and the proportion of metastatic
tumours was also high, mainly in Estonia and Slovakia.
The mean excess hazard of death by time since diagnosis was similar in Europe and the US
for women with early node-negative disease, large node-negative disease or node-positive
disease, and up to five years after diagnosis. The hazard was somewhat higher in Eastern
Europe for locally advanced disease, and much higher for metastatic disease, especially in
the first three years after diagnosis. Adjustment for the number of examined lymph nodes,
necessarily restricted to women who underwent lymphadenectomy (86%), did not modify
this pattern, either overall, or within each category of stage. In other words, the geographic
pattern in the mean excess hazard of death was not affected by the number of nodes
examined during lymphadenectomy (data not shown). This suggests that, in contrast with
the findings from the study of women diagnosed in 19904, stage migration does not affect
the comparison of stage-specific survival between European regions and the US. This could
be because the recording of stage has become more homogeneous, or because the quality
and completeness of diagnostic investigation is less variable now than previously.
The mean excess hazard of death for women with late-stage disease was very high in
Eastern Europe. This suggests that fewer effective treatment options were available for these
women, although higher levels of co-morbidity may have restricted therapeutic options.
Hormonal treatment and adjuvant chemotherapy were used more extensively in Slovakia,
Estonia and Poland than in other European countries, and not just for node-positive and
estrogen-receptor positive disease. Mastectomy was often used instead of breast-conserving
surgery and radiotherapy, in part because radiotherapy facilities were not always available.
Total national expenditure on health was low, and this is also likely to have affected the
quality of treatment6.
Allemani et al. Page 10
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Data on stage were remarkably complete, because they were collected directly from clinical
records. Complete data on stage and lymph nodes were unavailable for all but 5–11% of
women in the 5 broad European regions, although for up to 20% in 3 of the 26 European
registries. However, exclusion of women with unknown stage or lymph node status did not
change the geographic pattern of the excess hazard of death within any of the categories for
which stage was known. More complex analyses after imputation of missing values are
unlikely to change this picture.
Pattern of care studies and survival have been conducted separately in Europe5,6 and the
US24. Here, we could make a direct comparison between Europe and the US with data on
stage at diagnosis and treatment collected and coded with the same rules.
Overall, women received breast-conserving surgery and radiotherapy for early node-
negative breast cancer somewhat more often in Europe (55%) than the US (49%), but the
distribution by age was similar. The lower proportion in the US is mainly determined by
Louisiana (37%) and South Carolina (34%) and may be explained by the attitude of some
US clinicians during the late 1990s, when radiotherapy may have been considered
unnecessary after breast-conserving surgery10. Another explanation may be the paucity of
radiotherapy centres and/or the distance of the nearest radiotherapy facility25 in these two
states.
After adjusting for age and tumour size within the category of early node-negative disease,
the odds of being treated with breast-conserving surgery and radiotherapy were almost 60%
higher in Western Europe than Southern Europe (reference), 20–40% lower in the US and
Northern Europe, and more than 80% lower in Eastern Europe.
In Denmark, the low level of breast-conserving surgery and radiotherapy was probably
related to the fact that most breast cancers were treated in local or regional hospitals (not
specialist centres), rather than any lack of radiotherapy facilities, although the Danish
national cancer plan of 2000 recognised the need to modernize and expand radiotherapy
services. Most women receiving breast-conserving surgery also received radiotherapy, but
breast-conserving surgery was hardly ever done in areas where breast cancer screening was
not performed26.
About 90% of women aged less than 50 years with node-positive disease received
chemotherapy in both Europe and the US, in accordance with contemporary clinical
protocols27.
The proportion of women aged 50–99 years with positive lymph nodes who received
chemotherapy was notably higher in the US (60% vs. 46%). The proportion was similar in
all 7 states, but slightly lower in Illinois and Rhode Island. The finding of more active
treatment for older women in the US echoes the finding for women diagnosed in 1990, and
may indicate the importance of health insurance programs such as MEDICARE. The US
National Institutes of Health had also recommended chemotherapy for node-positive breast
cancer in 198528.
Allemani et al. Page 11
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
In the late 1990s, tamoxifen was recommended for estrogen-receptor positive tumours on
both sides of the Atlantic29,30, especially for women aged over 50 years. In the US, the
proportion of women aged less than 50 years with ER+ tumours treated with hormonal
therapy was 58%, higher than in Europe (44%).
The low proportion of women with early stage disease who receive breast-conserving
surgery is correlated with total national expenditure on health6. The wider use of
chemotherapy and hormonal treatment may reflect the fact that costs are lower than for
surgery and radiotherapy. Taken with the findings of this study, this suggests that low
healthcare expenditure in Eastern European countries may have had an important effect on
the quality of breast cancer treatment, and on survival.
Differences in breast cancer survival between Europe and the US in the late 1990s were
mainly explained by lower survival in Eastern Europe, where low healthcare expenditure
may have constrained the quality of breast cancer treatment. Similarly wide variation has
also been reported within the US, where non-Hispanic Black women were less likely to
receive guideline-concordant treatment than non-Hispanic White women8.
The need for population-based data on stage and treatment is recognised by clinicians and
epidemiologists. High-resolution studies still seem to be the only valid way to collect this
information. More funding should be directed to help cancer registries obtain timely high-
resolution data for all registered patients.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
Some of the data for this study were collected with the support of the Compagnia di San Paolo, Turin, Italy. Support was also obtained from the Health Department of the Navarra Government, Spain (research grant 79/2000). Alleanza Contro il Cancro, the Italian Cancer Network (http://www.alleanzacontroilcancro.it) supported a CONCORD Working Group meeting in London, 29–30 September 2010. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention.
References
1. Cutler, SJ., editor. International symposium on end results of cancer therapy. Bethesda MD: National Cancer Institute; 1964. NCI Monograph 15
2. Gatta G, Capocaccia R, Coleman MP, Ries LAG, Hakulinen T, Micheli A, Sant M, Verdecchia A, Berrino F. Toward a comparison of survival in American and European cancer patients. Cancer. 2000; 89:893–900. [PubMed: 10951355]
3. Coleman MP, Quaresma M, Berrino F, Lutz J-M, De Angelis R, Capocaccia R, Baili P, Rachet B, Gatta G, Hakulinen T, Micheli A, Sant M, et al. Cancer survival in five continents: a worldwide population-based study (CONCORD). Lancet Oncol. 2008; 9:730–56. [PubMed: 18639491]
4. Sant M, Allemani C, Berrino F, Coleman MP, Aareleid T, Chaplain G, Coebergh JWW, Colonna M, Crosignani P, Danzon A, Federico M, Gafà L, et al. Breast carcinoma survival in Europe and the USA: a population-based study. Cancer. 2004; 100:715–22. [PubMed: 14770426]
5. Sant M. EUROCARE Working Group. Differences in stage and therapy for breast cancer across Europe. Int J Cancer. 2001; 93:894–901. [PubMed: 11519054]
Allemani et al. Page 12
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
6. Allemani C, Storm H, Voogd AC, Holli K, Izarzugaza I, Torrella-Ramos A, Bielska-Lasota M, Aareleid T, Ardanaz E, Colonna M, Crocetti E, Danzon A, et al. Variation in ‘standard care’ for breast cancer across Europe: a EUROCARE-3 high resolution study. Eur J Cancer. 2010; 46:1528–36. [PubMed: 20299206]
7. Sariego J. Regional variation in breast cancer treatment throughout the United States. Am J Surg. 2008; 196:572–4. [PubMed: 18809065]
8. Wu X, Richardson LC, Kahn AR, Fulton JP, Cress RD, Shen T, Wolf HJ, Bolick-Aldrich S, Chen VW. Survival difference between non-Hispanic black and non-Hispanic white women with localised breast cancer: the impact of guideline-concordant therapy. J Natl Med Assoc. 2008; 100:490–8. [PubMed: 18507201]
9. Lazovich D, Solomon CC, Thomas DB, Moe RE, White E. Breast conservation therapy in the United States following the 1990 National Institutes of Health consensus development conference on the treatment of patients with early-stage invasive breast carcinoma. Cancer. 1999; 86:628–37. [PubMed: 10440690]
10. Nattinger AB, Hoffmann RG, Kneusel RT, Schapira MM. Relation between the appropriateness of primary therapy for early-stage breast carcinoma and increased use of breast-conserving surgery. Lancet. 2000; 356:1148–53. [PubMed: 11030294]
11. Sant M, Allemani C, Santaquilani M, Knijn A, Marchesi F, Capocaccia R. EUROCARE Working Group. EUROCARE-4. Survival of cancer patients diagnosed in 1995–1999: results and commentary. Eur J Cancer. 2009; 45(Suppl 6):931–91. [PubMed: 19171476]
12. Spiessl, B.; Beahrs, OH.; Hermanek, P.; Hutter, RVP.; Scheibe, O.; Sobin, LH.; Wagner, KF., editors. TNM Atlas: illustrated guide to the TNM/pTNM classification of malignant tumours. Berlin: Springer Verlag; 1992.
13. Nelson CP, Lambert PC, Squire IB, Jones DR. Flexible parametric models for relative survival, with application in coronary heart disease. Stat Med. 2007; 26:5486–98. [PubMed: 17893893]
14. Estève, J.; Benhamou, E.; Raymond, L. Statistical methods in cancer research, volume IV. Descriptive epidemiology. Lyon: International Agency for Research on Cancer; 1994. IARC Scientific Publications No. 128
15. Pohar Perme M, Stare J, Estève J. On estimation in relative survival [epub ahead of print]. Biometrics. 2011 doi:10,1111/j.1541–0420.2011.01640.x.
16. Baili P, Micheli A, De Angelis R, Weir HK, Francisci S, Santaquilani M, Hakulinen T, Quaresma M, Coleman MP. CONCORD Working Group. Life-tables for world-wide comparison of relative survival for cancer (CONCORD study). Tumori. 2008; 94:658–68. [PubMed: 19112937]
17. Akaike H. A new look at the statistical model identification. IEEE Transactions on Automatic Control. 1974; 19:716–23.
18. Lambert PC, Royston P. Further development of flexible parametric models for survival analysis. Stata J. 2009; 9:265–90.
19. Danieli C, Remontet L, Bossard N, et al. Estimating net survival: the importance of allowing for informative censoring. Stat Med. 2011 in press.
20. Corazziari I, Quinn MJ, Capocaccia R. Standard cancer patient population for age standardising survival ratios. Eur J Cancer. 2004; 40:2307–16. [PubMed: 15454257]
21. National Cancer Institute. SEER Stat - cancer incidence public use database 1973–95. Bethesda, MD: National Cancer Institute; 1998. version 1.1
22. Merrill RM, Dearden KA. How representative are the surveillance, epidemiology, and end results (SEER) Program cancer data of the United States? Cancer Causes Control. 2004; 15:1027–34. [PubMed: 15801487]
23. Christensen LH, Engholm G, Cortes R, Ceberg J, Tange U, Andersson M, Bladström A, Mouridsen HT, Möller T, Storm H. Reduced mortality for women with mammography-detected breast cancer in east Denmark and south Sweden. Eur J Cancer. 2006; 42:2773–80. [PubMed: 16989996]
24. Alley LG, Chen VW, Wike JM, Schymura MJ, Rycroft R, Shen T, Bolick-Aldrich S, Roshala W, Fulton JP. CDC and NPCR’s breast, colon, and prostate cancer data quality and patterns of care study: overview and methodology. J Registry Manag. 2007; 34:148–57.
Allemani et al. Page 13
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
25. Nattinger AB, Kneusel RT, Hoffmann RG, Gilligan MA. Relationship of distance from radiotherapy facility and initial breast cancer treatment. J Natl Cancer Inst. 2001; 93:1344–6. [PubMed: 11535710]
26. Tange UB, Jensen MB, Vejborg IM, Rank FE, Blichert-Toft M, Mouridsen HT, Lynge E. Clinical impact of introduction of mammography screening in a non-screening country with special reference to the Copenhagen service mammography screening programme. Scand J Surg. 2002; 91:293–303. [PubMed: 12449474]
27. Update of the NCCN guidelines for treatment of breast cancer. Oncology. 1997; 11:199–220. [PubMed: 9430190]
28. Consensus conference: adjuvant chemotherapy for breast cancer. J Amer Med Assoc. 1985; 254:3461–3.
29. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy. Lancet. 1992; 339:1–15. 71–85. [PubMed: 1345950]
30. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet. 1998; 352:930–42. [PubMed: 9752815]
Allemani et al. Page 14
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Figure 1. Five-year age-standardised net survival (%), women diagnosed with primary invasive breast
cancer in Europe and the US in the late 1990s: country and region
Allemani et al. Page 15
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Allemani et al. Page 16
Tab
le 1
Stag
e at
dia
gnos
is f
or w
omen
with
inva
sive
pri
mar
y br
east
can
cer,
Eur
ope
and
US:
ava
ilabi
lity
(%)
of d
ata
and
dist
ribu
tion.
EU
RO
PE
Reg
istr
yP
erio
d of
dia
gnos
isM
orph
olog
ical
ly v
erif
ied
Stag
e da
ta a
vaila
ble
Ear
ly
node
-ne
gati
ve
(T1
N0
M0)
Lar
ge
node
-ne
gati
ve
(T2-
3 N
0 M
0)
Nod
e-po
siti
ve
(T1-
3 N
+ M
0)
Loc
ally
ad
vanc
ed
(T4
any
N M
0)M
etas
tase
s (M
1)U
nsta
ged
No.
%%
%%
%%
%%
Den
mar
kN
atio
nal
1994
500
9994
2811
2824
36
Est
onia
Nat
iona
l19
9752
279
9417
1535
1711
6
Fin
land
Nat
iona
l19
96–1
997
552
9582
369
304
218
Fra
nce
Bas
-Rhi
n19
9517
595
9742
1529
37
3
Côt
e d’
Or
1996
–199
752
199
9643
1431
53
4
Dou
bs19
9723
497
9834
2134
27
2
Isèr
e19
9724
395
9549
1230
04
5
Tar
n19
9723
198
9436
1628
68
6
Icel
and
Nat
iona
l19
95–1
998
458
9790
3613
351
410
Ital
yFi
renz
e19
9733
094
8235
925
84
18
Gen
ova
1996
523
9392
3414
2710
78
Mod
ena
1997
478
9795
4810
323
35
Pale
rmo
1999
580
9389
2613
359
611
Rag
usa
1996
–199
839
287
7820
1336
36
22
Var
ese
1996
–199
71,
126
9792
3212
3310
58
Net
herl
ands
Ein
dhov
en19
97–1
998
1,28
199
9743
1331
64
3
NE
Net
herl
ands
1997
2,23
792
9232
1830
67
8
Pol
and
Cra
cow
1997
–199
861
984
9323
1344
75
7
War
saw
1996
597
9688
2313
426
412
Slov
akia
Nat
iona
l19
9655
197
9822
1436
819
2
Slov
enia
Nat
iona
l19
9788
282
9123
1532
1110
9
Spai
nB
asqu
e C
ount
ry19
9654
110
094
2818
368
56
Cas
tello
n19
95–1
998
769
9896
3316
346
74
Gra
nada
1996
–199
750
095
9316
2238
116
7
Nav
arra
1996
–199
750
099
9339
1331
46
7
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Allemani et al. Page 17
EU
RO
PE
Reg
istr
yP
erio
d of
dia
gnos
isM
orph
olog
ical
ly v
erif
ied
Stag
e da
ta a
vaila
ble
Ear
ly
node
-ne
gati
ve
(T1
N0
M0)
Lar
ge
node
-ne
gati
ve
(T2-
3 N
0 M
0)
Nod
e-po
siti
ve
(T1-
3 N
+ M
0)
Loc
ally
ad
vanc
ed
(T4
any
N M
0)M
etas
tase
s (M
1)U
nsta
ged
No.
%%
%%
%%
%%
Swed
enN
atio
nal
1994
500
9490
3611
2514
510
E
urop
ean
regi
stri
es15
,842
9492
3214
338
68
N
orth
ern
Eur
ope
2,01
096
8934
1129
113
11
W
este
rn E
urop
e4,
922
9595
3716
305
65
So
uthe
rn E
urop
e6,
621
9491
3014
338
69
E
aste
rn E
urop
e2,
289
8993
2114
399
97
US
Stat
e
Cal
ifor
nia
1997
458
9992
4312
284
58
Col
orad
o19
9748
599
9445
1426
54
6
Illin
ois
1997
467
9988
3716
226
812
Lou
isia
na19
9749
299
8837
1725
46
12
New
Yor
k19
9744
898
8133
1029
35
19
Rho
de I
slan
d19
9740
399
8742
1127
34
13
Sout
h C
arol
ina
1997
367
9894
3818
285
56
U
S re
gist
ries
3,12
099
8939
1426
45
11
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Allemani et al. Page 18
Tab
le 2
No.
of
lym
ph n
odes
exa
min
ed a
mon
g w
omen
with
bre
ast c
ance
r w
ho u
nder
wen
t lym
phad
enec
tom
y, a
nd d
istr
ibut
ion
(%)
of tu
mou
r si
ze in
wom
en w
ith
earl
y, n
ode-
nega
tive
(T1N
0M0)
bre
ast c
ance
r tr
eate
d by
sur
gery
: Eur
ope
and
US
Lym
phad
enec
tom
y10
or
mor
e ly
mph
nod
es e
xam
ined
Wom
en w
ith
earl
y no
de-n
egat
ive
dise
ase
trea
ted
by s
urge
ry1
Les
s th
an 5
mm
(T
1a)
5 to
10m
m (
T1b
)O
ver
10m
m u
p to
20m
m (
T1c
)
EU
RO
PE
Reg
istr
yN
o.%
No.
%%
%
Den
mar
kN
atio
nal
445
5914
27
2568
Est
onia
Nat
iona
l38
323
870
1780
Fin
land
Nat
iona
l46
133
200
434
63
Fra
nce
Bas
-Rhi
n16
866
745
2372
Côt
e d’
Or
489
4722
68
4052
Dou
bs22
035
796
2767
Isèr
e22
767
118
545
50
Tar
n20
875
835
3758
Icel
and
Nat
iona
l39
365
165
528
64
Ital
yFi
renz
e25
693
116
417
66
Gen
ova
454
8417
89
1858
Mod
ena
459
8122
69
3456
Pale
rmo
568
7714
89
1846
Rag
usa
299
8077
617
62
Var
ese
969
9135
94
2570
Net
herl
ands
Ein
dhov
en1,
172
6054
24
2865
NE
Net
herl
ands
1,89
650
715
218
48
Pol
and
Cra
cow
516
6714
46
2668
War
saw
487
8313
96
2265
Slov
akia
Nat
iona
l45
627
120
526
69
Slov
enia
Nat
iona
l68
889
200
418
74
Spai
nB
asqu
e C
ount
ry48
375
151
525
64
Cas
tello
n70
778
256
628
63
Gra
nada
431
8682
222
62
Nav
arra
430
8619
311
2465
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Allemani et al. Page 19
Lym
phad
enec
tom
y10
or
mor
e ly
mph
nod
es e
xam
ined
Wom
en w
ith
earl
y no
de-n
egat
ive
dise
ase
trea
ted
by s
urge
ry1
Les
s th
an 5
mm
(T
1a)
5 to
10m
m (
T1b
)O
ver
10m
m u
p to
20m
m (
T1c
)
EU
RO
PE
Reg
istr
yN
o.%
No.
%%
%
Swed
enN
atio
nal
422
4917
94
3660
E
urop
ean
regi
stri
es13
,687
664,
999
526
61
US
Stat
e
Cal
ifor
nia
397
7919
88
3159
Col
orad
o39
978
215
1228
57
Illin
ois
376
7817
113
3250
Lou
isia
na41
575
181
732
60
New
Yor
k33
583
150
1134
53
Rho
de I
slan
d31
376
167
1125
62
Sout
h C
arol
ina
296
7613
89
2362
US
regi
stri
es2,
531
781,
220
1029
57
1 Perc
enta
ges
do n
ot a
dd to
100
%: e
arly
nod
e-ne
gativ
e tu
mou
rs w
ith n
o pr
ecis
e da
ta o
n tu
mou
r si
ze a
re n
ot s
how
n
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Allemani et al. Page 20
Tab
le 3
Bre
ast-
cons
ervi
ng s
urge
ry p
lus
radi
othe
rapy
(B
CS+
RT
) in
ear
ly n
ode-
nega
tive
brea
st c
ance
r (T
1N0M
0), b
y ag
e: E
urop
e an
d U
S
EU
RO
PE
Reg
istr
y
All
wom
enSu
rgic
ally
tre
ated
No.
Any
sta
geE
arly
nod
e-ne
gati
ve
No.
%
All
ages
(15
–99
year
s)15
–69
year
s70
–99
year
s
No.
%
BC
S +
RT
No.
%
BC
S +
RT
No.
%
BC
S +
RT
No.
%N
o.%
No.
%
Den
mar
kN
atio
nal
500
487
9714
229
3827
122
8635
2920
143
15
Est
onia
Nat
iona
l52
240
477
8722
89
7384
710
1416
17
Fin
land
Nat
iona
l55
252
094
200
3812
060
163
8211
168
3719
924
Fra
nce
Bas
-Rhi
n17
516
594
7445
4764
6182
4066
1318
754
Côt
e d’
Or
521
501
9622
645
189
8419
385
164
8533
1525
76
Dou
bs23
422
596
7935
6278
6380
5384
1620
956
Isèr
e24
323
396
118
5197
8210
186
8483
1714
1376
Tar
n23
122
095
8338
7084
5870
4984
2530
2184
Icel
and
Nat
iona
l45
843
896
165
3874
4513
984
7252
2616
28
Ital
yFi
renz
e33
029
991
116
3986
7485
7370
8231
2716
52
Gen
ova
523
487
9317
837
123
6914
581
107
7433
1916
48
Mod
ena
478
465
9722
649
124
5517
778
114
6449
2210
20
Pale
rmo
580
555
9614
827
104
7012
685
9172
2215
1359
Rag
usa
392
337
8677
2341
5362
8137
6015
194
27
Var
ese
1,12
61,
053
9435
934
158
4428
579
138
4874
2120
27
Net
herl
ands
Ein
dhov
en1,
281
1,21
995
542
4435
966
428
7930
070
114
2159
52
NE
Net
herl
ands
2,23
71,
989
8971
536
366
5158
081
330
5713
519
3627
Pol
and
Cra
cow
619
518
8414
428
1611
119
8315
1325
171
4
War
saw
597
532
8913
926
2820
121
8727
2218
131
6
Slov
akia
Nat
iona
l55
148
588
120
2542
3599
8338
3821
184
19
Slov
enia
Nat
iona
l88
271
881
200
2812
161
169
8511
769
3116
413
Spai
nB
asqu
e C
ount
ry54
150
694
151
3010
368
131
8791
6920
1312
60
Cas
tello
n76
973
095
256
3598
3822
086
9342
3614
514
Gra
nada
500
458
9282
1837
4572
8836
5010
121
10
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Allemani et al. Page 21
EU
RO
PE
Reg
istr
y
All
wom
enSu
rgic
ally
tre
ated
No.
Any
sta
geE
arly
nod
e-ne
gati
ve
No.
%
All
ages
(15
–99
year
s)15
–69
year
s70
–99
year
s
No.
%
BC
S +
RT
No.
%
BC
S +
RT
No.
%
BC
S +
RT
No.
%N
o.%
No.
%
Nav
arra
500
459
9219
342
149
7717
390
140
8120
109
45
Swed
enN
atio
nal
500
471
9417
938
8246
138
7772
5241
2310
24
E
urop
ean
regi
stri
es15
,842
14,4
7491
4,99
935
2,74
255
4,10
382
2,43
159
896
2231
135
US
Stat
e
Cal
ifor
nia
458
440
9619
845
106
5413
870
7756
6030
2948
Col
orad
o48
547
097
215
4611
453
163
7697
6052
2417
33
Illin
ois
467
436
9317
139
9455
117
6873
6254
3221
39
Lou
isia
na49
247
597
181
3867
3711
966
5445
6234
1321
New
Yor
k44
843
096
150
3577
5195
6355
5855
3722
40
Rho
de I
slan
d40
338
094
167
4497
5810
965
7064
5835
2747
Sout
h C
arol
ina
367
351
9613
839
4734
9670
3536
4230
1229
U
S re
gist
ries
3,12
02,
982
961,
220
4160
249
837
6946
155
383
3114
137
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Allemani et al. Page 22
Table 4
Odds ratio (OR) for women with early node-negative disease (T1N1M0) being treated with breast-conserving
surgery and radiotherapy (vs. any other surgical procedure, with or without radiotherapy) in each jurisdiction,
adjusted for age and tumour size
No.1 OR 95% CI
Jurisdiction
Northern Europe 681 0.60 0.50 0.72
Western Europe 1,595 1.57 1.36 1.81
Southern Europe 1,848 1
Eastern Europe 477 0.16 0.12 0.20
US 1,185 0.80 0.69 0.94
Age (years)
15–39 244 1.33 0.99 1.78
40–49 1,039 1.44 1.21 1.70
50–59 1,558 1.38 1.19 1.60
60–69 1,614 1
70–99 1,331 0.48 0.41 0.56
Tumour size
Less than 5mm (T1a) 380 0.94 0.75 1.17
5–10mm (T1b) 1,650 1.31 1.16 1.48
>10mm, up to 20mm (T1c) 3,756 1
1Number of women with early node-negative disease who were operated, with information on tumour size available
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Allemani et al. Page 23
Tab
le 5
Che
mot
hera
py in
nod
e-po
sitiv
e di
seas
e an
d en
docr
ine
trea
tmen
t in
estr
ogen
-rec
epto
r-po
sitiv
e di
seas
e, b
y ag
e: r
egis
try
and
coun
try
Wom
en w
ith
node
-pos
itiv
e tu
mou
rsW
omen
wit
h es
trog
en-r
ecep
tor-
posi
tive
tum
ours
15–4
9 ye
ars
50–9
9 ye
ars
No.
End
ocri
netr
eatm
ent
15–4
9 ye
ars
50–9
9 ye
ars
EU
RO
PE
Reg
istr
y
No.
Che
mo-
ther
apy
Tot
alC
hem
o-th
erap
yT
otal
Che
mo-
ther
apy
Tot
alE
ndoc
rine
trea
tmen
tT
otal
End
ocri
netr
eatm
ent
No.
%N
o.%
No.
%N
o.%
No.
%N
o.%
No.
%N
o.%
No.
%N
o.%
Den
mar
kN
atio
nal
204
4321
3517
1954
169
8324
1434
011
534
5215
48
288
011
139
Est
onia
Nat
iona
l30
023
679
8127
7694
219
7316
073
110
9485
3431
2471
7669
7092
Fin
land
Nat
iona
l18
971
3852
2841
7913
772
3022
376
125
3389
2421
2428
776
104
36
Fra
nce
Bas
-Rhi
n63
4876
1727
1710
046
7331
67n/
an/
an/
an/
an/
an/
an/
an/
an/
an/
an/
a
Côt
e d’
Or
194
110
5767
3558
8712
765
5241
396
220
5610
627
3331
290
7318
764
Dou
bs94
5963
2527
2184
6973
3855
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Isèr
e78
5064
2026
1995
5874
3153
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Tar
n86
5260
2327
2191
6373
3149
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
n/a
Icel
and
Nat
iona
l17
897
5459
3353
9011
967
4437
303
162
5377
2532
4222
675
130
58
Ital
yG
enov
a119
313
972
4624
4291
147
7697
66
Mod
ena
169
129
7645
2740
8912
473
8972
320
221
6975
2359
7924
577
162
66
Pale
rmo
252
198
7977
3175
9717
569
123
7020
914
871
7033
5376
139
6795
68
Var
ese
455
250
5513
129
9069
324
7116
049
685
246
3615
723
4227
528
7720
439
Net
herl
ands
Ein
dhov
en47
718
138
144
3013
392
333
7048
1455
218
934
149
2718
1240
373
171
42
NE
Net
herl
ands
823
323
3923
629
220
9358
771
103
18n/
an/
an/
an/
an/
an/
an/
an/
an/
an/
an/
a
Pol
and
Cra
cow
336
184
5584
2574
8825
275
110
4410
466
6322
2113
5982
7953
65
War
saw
290
157
5496
3380
8319
467
7740
8961
6926
2910
3863
7151
81
Slov
akia
Nat
iona
l28
821
976
9934
9192
189
6612
868
9349
5334
3712
3559
6337
63
Slov
enia
Nat
iona
l40
228
270
108
2710
698
294
7317
660
385
227
5988
2324
2729
777
203
68
Spai
nB
asqu
e C
ount
ry22
819
083
8738
8497
141
6210
675
260
213
8276
2949
6418
471
164
89
Cas
tello
n32
724
073
8526
8296
242
7415
865
355
290
8286
2470
8126
976
220
82
Gra
nada
237
178
7572
3071
9916
570
107
6515
712
781
4529
2964
112
7198
88
Nav
arra
169
138
8267
4067
100
102
6071
7031
725
279
8627
7284
231
7318
078
Swed
enN
atio
nal
159
4528
3421
2779
125
7918
1424
812
350
4117
717
207
8311
656
Int J Cancer. Author manuscript; available in PMC 2016 January 09.
Author M
anuscriptA
uthor Manuscript
Author M
anuscriptA
uthor Manuscript
Allemani et al. Page 24
Wom
en w
ith
node
-pos
itiv
e tu
mou
rsW
omen
wit
h es
trog
en-r
ecep
tor-
posi
tive
tum
ours
15–4
9 ye
ars
50–9
9 ye
ars
No.
End
ocri
netr
eatm
ent
15–4
9 ye
ars
50–9
9 ye
ars
EU
RO
PE
Reg
istr
y
No.
Che
mo-
ther
apy
Tot
alC
hem
o-th
erap
yT
otal
Che
mo-
ther
apy
Tot
alE
ndoc
rine
trea
tmen
tT
otal
End
ocri
netr
eatm
ent
No.
%N
o.%
No.
%N
o.%
No.
%N
o.%
No.
%N
o.%
No.
%N
o.%
E
urop
ean
regi
stri
es6,
191
3,61
958
1,79
029
1,60
790
4,40
171
2,01
246
5,29
92,
928
551,
313
2557
244
3,98
675
2,35
659
US
Stat
e
Cal
ifor
nia
154
107
6955
3646
8499
6461
6228
715
755
6824
3146
219
7612
658
Col
orad
o15
511
373
5133
4894
104
6765
6329
019
266
7325
4764
217
7514
567
Illin
ois
133
8765
4332
3991
9068
4853
233
129
5545
1923
5118
881
106
56
Lou
isia
na15
510
266
3825
3284
117
7570
6026
011
645
4015
1845
220
8598
45
New
Yor
k15
510
668
4730
4289
108
7064
5922
814
764
4218
2048
186
8212
768
Rho
de I
slan
d12
884
6634
2732
9494
7352
5530
124
581
6823
5276
233
7719
383
Sout
h C
arol
ina
121
8974
3529
3189
8671
5867
186
121
6539
2126
6714
779
9565
U
S re
gist
ries
1,00
168
869
303
3027
089
698
7041
860
1,78
51,
107
6237
521
217
581,
410
7989
063
n/a
- no
t ava
ilabl
e
1 Reg
istr
ies
wer
e ex
clud
ed if
dat
a on
trea
tmen
t wer
e un
avai
labl
e fo
r m
ore
than
20%
of
wom
en: G
enov
a (h
orm
onal
trea
tmen
t), F
iren
ze a
nd R
agus
a (b
oth
trea
tmen
ts)
Int J Cancer. Author manuscript; available in PMC 2016 January 09.